This proposal includes related studies in hamsters and humans with gallstones. The thrust of the hamster studies is the rapid evaluation of the efficacy and mechanism of action of agents that prevent or dissolve cholesterol gallstones in our established animal model. The thrust of the human studies is an evaluation of methods to enhance the dissolution efficacy of ursodeoxycholic acid (UDCA) treatment in patients with gallstones. Hamsters receiving a low dose of ethinyl estradiol and a 3-fold increase in dietary cholesterol produce saturated bile and cholesterol gallstones indistinguishable by scanning electron microscopy from human cholesterol gallstones. Chenodeoxycholic acid (CDCA) and UDCA which prevent gallstone formation in hamsters and dissolve stones in humans will be tested in hamsters for dissolution and compared to cholic acid. Dose-response studies will be done with CDCA and UDCA. The action of the 3-beta, 7-beta and 3-beta, 7-alpha epimers of CDCA and UDCA, 7-alpha cholanoic acid, and the non-ionic lipophilic resin XAD-2 also will be studied in hamsters. Other potential agents (e.g. Zanchol, bran, tricaprylin, and glycerophosphate) will be tested. Biliary and hepatic morphology and lipid and bile acid composition and the hepatic rate-limiting enzymes for cholesterol synthesis (HMG-CoA reductase) and bile acid synthesis (cholesterol 7-alpha-hydroxylase) will be determined. In addition, the bile acid pool size, intestinal HMG-CoA reductase, and serum lipoprotein patterns will be determined. Forming and dissolving gallstones will be compared by scanning electron microscopy to study aggregation of cholesterol crystals. In the clinical trial the effects of bran, medium-chain triglycerides, and a low cholesterol diet on biliary lipids and on the dissolution efficacy of UDCA will be detemined. In addition, the effect of a brief period of increased dietary cholesterol on biliary lipids will be measured in a dose-response study. Biliary lipid secretion, bile acid kinetics, bile saturation, and serum lipoprotein profiles will be determined in patients before and during the experimental periods.